This invention relates to water-soluble polymer conjugates of biologically active molecules.
Artelinic acid, which is described in U.S. Pat. No. 4,791,135 and shown below, is a potentially useful drug for treatment of malaria. In addition, artelinic acid may prove useful as an anti-viral, anti-cancer, anti-bacterial or anti-fungal agent. One problem in using artelinic acid as a drug is its low water solubility. This can be improved by using the salt form, sodium artelinate. However, this salt is not highly soluble at physiological pH and a higher pH is required for desirable solubility levels. 
There is thus a need for derivatives of artelinic acid which are highly water-soluble at physiological pH and which can be delivered over a range of useful doses.
The present invention provides water-soluble polymer conjugates of the anti-malarial drug, artelinic acid, using water soluble and non-peptidic polymer backbones, such as poly(ethylene glycol). The conjugates having an ester linkage between the artelinic acid moiety and the polymer backbone are prodrugs, meaning that the ester linkage hydrolyzes to liberate the parent drug, artelinic acid.
The polymer conjugates of artelinic acid comprise a water soluble and non-peptidic polymer backbone, such as PEG, having at least one terminus bonded to the following structure: 
wherein L is the point of attachment to the terminus of the polymer backbone and Z is a linker, such as O or NH. Examples of the polymer backbone include poly(alkylene glycol), poly(oxyethylated polyol), poly(olefinic alcohol), poly(vinylpyrrolidone), poly(hydroxypropylmethacrylamide), poly(xcex1-hydroxy acid), poly(vinyl alcohol), polyphosphazene, polyoxazoline, poly(N-acryloylmorpholine), and copolymers, terpolymers, and mixtures thereof.
The polymer conjugates of the invention may comprise linear polymer backbones, such as mPEG or bifunctional PEG, or multi-arm polymer backbones. The invention includes heterobifunctional polymer conjugates wherein one terminus of the polymer backbone is attached to the artelinic acid moiety and the other terminus is functionalized with a different moiety. Additionally, the invention includes homobifunctional polymer conjugates, wherein both termini of the polymer backbone are bonded to artelinic acid moieties.
The invention also provides a method of forming a polymer conjugate of artelinic acid. The method includes the step of providing a water soluble and non-peptidic polymer backbone having at least one terminus bonded to a functional group reactive with a carboxylic acid group, such as hydroxyl or amine. The polymer backbone is reacted with artelinic acid to form a polymer conjugate of artelinic acid having, for example, an amide or ester linkage between the polymer backbone and the artelinic acid moiety.
The polymer conjugates of the invention can be used to treat malaria in a mammal by administering to the mammal an effective amount of the above-described polymer conjugates of artelinic acid. Examples of methods of administering the conjugate include subcutaneously, transdermally, intravenously, orally, or by inhalation. In one embodiment, the conjugate is administered in the form of a hydrogel.